Process for the manufacture of pharmaceutically active compounds

ABSTRACT

According to the present invention there are provided novel processes for the manufacture of the compound of formula 1 
     
       
         
         
             
             
         
       
     
     as well as novel synthesis routes for key intermediates used in those processes.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.09167054.7, filed Aug. 3, 2009, and European Patent Application No.09175101.6, filed Nov. 5, 2009, both of which are hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention is related to synthesis routes to obtain thecompound propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(formula 1).

The synthesis of the compound of formula (1) has been described beforein WO 2007002433 and WO 2007002325.

However, the known synthesis routes may not be readily adapted for useon an industrial scale.

SUMMARY OF THE INVENTION

The present invention relates in part to a process for the manufactureof the compound of formula (1),

comprising the steps of reacting the compound of formula (5),

with 4-chlorophenylboronic acid in the presence of a palladium catalystto produce the compound of formula (6),

andcleaving the 2,6-dichlorobenzamide group in said compound of formula (6)to produce the compound of formula (1).

The present invention also relates in part to a compound of formula (A),

The present invention further relates in part to a compound of formula(B)

In addition, the present invention relates to a composition comprisingthe compound of formula (1) and the compound of formula (B).

The present invention also relates to an analytical method for thedetection of whether the process as described above has been used in themanufacture of the compound of formula (1), said method comprisingobtaining a sample from a medicament primarily containing the compoundof formula (1) as active ingredient, and applying a suitable analyticalmethod in order to detect whether said sample contains the compound offormula (B), wherein the presence of any amount of the compound offormula (B) indicates that the process has been used.

The present invention further relates to a process for the manufactureof compound (I),

comprising the steps of:aa) reacting the compound of formula (II),

with the compound of formula (III),

in the presence of a catalyst, copper(I)iodide and a base, to producethe compound of formula (IV),

bb) reacting said compound of formula (IV) in the presence of aqueousalkali metal hydroxide at 50-90° C. and under reduced pressure toproduce the compound of formula (V),

andcc) reacting said compound of formula (V) in the presence of aqueousalkali metal hydroxide or a strong base to produce the compound offormula (1);whereinR¹ and R² are each independently a C1-C4 alkyl, and

X is —Br or —Cl.

In addition, the present invention relates to a compound of formula(IV),

whereinR¹ and R² are each independently a C1-C4 alkyl, and

X is —Br or —Cl. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides new and improved synthesis routes for thecompound of formula (1), which employ reaction conditions which areparticularly amenable to being carried out on an industrial scale.

According to the present invention, there is provided a process for themanufacture of the compound of formula (1),

comprising the steps of reacting the compound of formula (5),

with 4-chlorophenylboronic acid (5a, scheme 1) in the presence of apalladium catalyst to produce the compound of formula (6),

andcleaving the 2,6-dichlorobenzamide group in said compound of formula(6), for example using ammonia, to produce the compound of formula (1).

The process according to the present invention efficiently uses startingmaterials, avoids formation of high quantities of undesirableby-products, provides high throughput and good product yields and cansafely be carried out in large scale production. It is also lessexpensive, and, due to the efficient use of starting materials,environmentally friendlier than processes disclosed in the prior art.

The term “palladium catalyst” as used herein means any suitablepalladium (Pd) catalyst, preferablybis(triphenylphosphin)palladium(II)dichloride ((PPh₃)₂PdCl₂) and Pd oncharcoal. Preferably, the amount of (PPh₃)₂PdCl₂ is about 0.0025equivalents with respect to compound of formula (5).

The compound of formula (5) can be obtained according to methods knownto the person of skill in the art of organic chemistry. In aparticularly preferred embodiment according to the present invention,the compound of formula (5) is obtained by reacting the compound offormula (2),

with a suitable activating agent (e.g., oxalylchloride ((COCl)₂)) toproduce the corresponding acid chloride, then reacting said acidchloride with 5-Bromo-7-azaindole (formula 3) and a suitable couplingagent (e.g., aluminium trichloride) to produce the compound of formula(4)

andreacting said compound of formula (4) with 2,6-dichlorobenzoylchlorideunder conditions suitable to produce the compound of formula (5).

In another particularly preferred embodiment according to the presentinvention there is provided the process for the manufacture of thecompound of formula (1), wherein

a) the compound of formula (2)

is reacted in a suitable solvent (e.g., methylenechloride (CH₂Cl₂)) witha suitable activating agent (e.g., Vilsmeier's salt prepared in situfrom oxalylchloride ((COCl)₂ and N,N-Dimethylformamide (DMF)) to producethe corresponding acid chloride, then reacting said acid chloride with5-bromo-7-azaindole (formula 3) in the presence of a suitable activatingagent (e.g., aluminium trichloride) to produce the compound of formula(4),

b) reacting said compound of formula (4) i with2,6-dichlorobenzoylchloride in the presence of a suitable base (e.g.n-Tripropylamine (n-Pr₃N)) and suitable catalyst (e.g.N,N-Dimethylaminopyridine (DMAP)) to produce the compound of formula(5),

c) reacting said compound of formula (5) with 4-chlorophenylboronic acidin the presence of a suitable palladium catalyst (e.g., (PPh₃)₂PdCl₂) toproduce the compound of formula (6)

and

d) reacting said compound of formula (6) with ammonia (NH₃) or a primaryor secondary amine (e.g. dimethylamine) in an alcohol (methanol orethanol) solution diluted with a polar aprotic solvent like DMA toproduce the compound of formula (1).

In a preferred embodiment according to the present invention, theabove-mentioned reaction step c) is carried out in a 2 phase reactionmixture comprising an non-polar aprotic solvent such as anisole ortoluene and aqueous sodium or potassium carbonate (Na₂CO₃, K₂CO₃).

The compounds (4), (5) and (6) are novel and each form an embodiment ofthe present invention.

The process according to the present invention can be summarizedaccording to the following reaction scheme (scheme 1) wherein, unlessexplicitly otherwise stated, all abbreviations and expressions have themeanings well known to the person of skill in the art of organicchemistry. All reaction partners and auxiliary agents (like i.e.catalysts, solvents) are commercially available.

According to the present invention, the first reaction under step a) isthe formation of an acid chloride of the carboxylic acid of formula (2).The reaction can be carried out employing a suspension of the compoundof formula (2) in suitable medium, e.g., methylenechloride (CH₂Cl₂)containing catalytic amounts of DMF, to which a solution ofoxalylchloride ((COCl)₂) in CH₂Cl₂ is slowly added. The addition istypically carried out at room temperature (RT) and the reaction mixtureis further stirred at RT until reaction completion (ca 6 h). The nextreaction is a Friedel-Crafts-Acylation. The freshly obtained solution ofacid chloride is added into a cooled (T=−12 to 5° C., preferably 0-5°C.) suspension of AlCl₃ and 5-Bromo-7-azaindole (3) in CH₂Cl₂. Thereaction mixture is allowed to heat up till RT due to released heat ofthe exothermic reaction and stirred for about 8 h to complete thereaction. The work-up and isolation procedure involves pouring of thereaction mixture into iced water, followed by extractive work-up andcrystallization of the compound of formula (4) fromTHF/methylenchloride/heptane. The compound of formula (4) can be furtherpurified by washing with i.e. heptane.

Reaction step b) starts with the preparation of a suspension of thecompound of formula (4) in a suitable aprotic solvent (e.g., toluene).Subsequently dimethylaminopyridine (DMAP), n-tripropylamine and2,6-dichlorobenzoylchloride are added at RT. The reaction mixture isstirred for about 60 minutes. After completion of the reaction anaqueous work-up is performed. Subsequently the toluene is slowlyevaporated from the organic solution, leading to the crystallization ofthe compound of formula (5) which can finally be isolated and furtherpurified through additional washing with e.g., cooled toluene.

Reaction step c) is a Pd-catalyzed Suzuki-coupling reaction of thecompound of formula (5) with 4-chlorophenylboronic acid (5a). Thereaction starts with the preparation of a suspension of4-chlorophenylboronic acid (5a) and the compound of formula (5) in anaprotic solvent, such as anisole, to which an aqueous solution of Na₂CO₃is added. The reaction mixture is heated slowly up to a temperature ofabout 85° C. During heating the Pd-catalyst is added at a temperaturebetween RT and around 70° C. Any suitable Pd-catalyst can be used, withbis(triphenylphosphin) palladium(II)dichloride ((PPh₃)₂PdCl₂) beingespecially preferred. The reaction mixture is stirred for about 120minutes at a temperature of about 85° C. to complete the reaction. Thehot bi-phasic reaction mixture is filtered to remove potentiallyprecipitated Pd. After aqueous work-up the organic (anisole) phase isconcentrated by evaporation, diluted with methanol and cooled down toabout 0° C. in order to initiate crystallization of the compound offormula (6). The precipitate is isolated, washed several times withcooled methanol and subsequently dried in vacuum. If needed the compoundof formula (6) can be further purified by re-crystallization fromToluene.

Reaction step d) is the removal of the 2,6-dichlorobenzamide protectiongroup. The reaction is carried out in a suspension/solution of thecompound of formula (6) in DMA/methanol (about 1:1-2:1) by addition ofabout 3-7 equivalents of a saturated ammonia solution (NH₃ in Methanol)at RT. The reaction mixture is stirred at about 55° C. until theprotection group is entirely cleaved (about 10 h). The resultingsolution is diluted with methanol and subsequently the ammonia isremoved via azeotropic distillation under reduced pressure. The residueis diluted with methanol and cooled to RT in order to initiatecrystallization of the compound of formula (1) which can then beisolated from the reaction mixture by filtration. The compound offormula (1) can be further purified by washing with e.g., methanol.

In another embodiment of the present invention there are identifiedspecific compounds (compounds (A) and (B) as specified below) which areby-products of the present synthesis method.

The compound of formula (A) may be formed during the reaction of thecompound of formula (5) with 4-Chlorophenylboronic acid (step c), scheme1). The compound of formula (B) is the de-protected form of formula (A)as obtained during reaction step d) as defined above (see also scheme1). These compounds, in particular the compound of formula (B) can serveas characteristic fingerprints for the use of the present process.

Trace amounts of the compound of formula (B) are typically found in thefinal product (formula (1)) as a pharmaceutically acceptable impurity inan amount of less than 0.30%, and usually in an amount of from about0.02% to about 0.15%, as identified by HPLC, provided said compound offormula (1) had been synthesized according to the present method.Therefore, while the impurity/trace amounts of the compound of formula(B) will not affect the pharmacological- or toxicity profile of anypotential future medicament or pharmaceutical preparation containing thecompound of formula (1), said compound may nevertheless serve as afingerprint in order to detect whether the present process has been usedto manufacture the compound of formula (1). The presence of the compoundof formula (B) will therefore allow for an unambiguous identification asto whether the present process has been used in the manufacture of thecompound of formula (1).

The compounds of formulas (A) and (B), in particular the compound offormula (B), may be detected in amounts of from about 0.02% to about0.15% by weight in a composition which otherwise contains >99% by weightof the compound of formula (1) formed using the process according to thepresent invention, and even following conventional purification methodsknown to the person of skill in the art. Therefore, trace amounts of thecompound of formula (B) may even be detectable in pharmaceuticalpreparations containing the compound of formula (1) when obtainedaccording to the present process. The compounds of formula (A) and (B)show the following NMR signals:

Compound A:

¹H-NMR (500 MHz, d6-DMSO): δ 0.99 (t, J=7.5 Hz, 3H), 1.72-1.82 (m, 2H),3.15-3.21 (m, 2H), 7.37 (t, J=9.0 Hz, 1H), 7.52-7.58 (m, 2H), 7.65-7.74(m, 4H), 7.76-7.85 (m, 4H), 7.87-7.92 (m, 2H), 8.58 (br. s, 1H), 8.82(d, J=2.5 Hz, 1H), 8.90 (br. s, 1H), 9.85 (br. s, 1H).

Compound B:

¹H-NMR (600 MHz, d6-DMSO): δ 0.97 (t, J=7.5 Hz, 3H), 1.70-1.80 (m, 2H),3.10-3.15 (m, 2H), 7.29 (t, J=8.7 Hz, 1H), 7.54-7.63 (m, 3H), 7.78-7.82(m, 2H), 7.83-7.90 (m, 4H), 8.25 (s, 1H), 8.70 (br. s, 1H), 8.79 (d,J=1.8 Hz, 1H), 9.78 (br. s, 1H), 13.02 (br. s, 1H).

Therefore, as a further embodiment according to the present invention,there are provided the compounds of formulae (A) and (B) as such.

In yet another embodiment the present invention provides an analyticalmethod for detecting whether the process according to the presentinvention has been used, characterized in that detectable levels of thecompounds of formula (A) and/or (B) as disclosed herein are generallypresent in any commercial pharmaceutical preparation comprisingprimarily the compound of formula (1) prepared employing the syntheticprocess disclosed herein. Preferably the analytical method is used todetect the compound of formula (B). Any suitable analytical method knownto the Organic Chemist may be applied, such as for exampleIR-spectroscopy, NMR-spectroscopy, Mass Spectrometry (MS) or HighPerformance Liquid Chromatography (HPLC). More preferably the analyticalmethod is based on High Performance Liquid Chromatography (HPLC), whichmay optionally be combined with a second analytical method such as forexample MS (HPLC-MS).

An aspect of the present invention is an analytical method for thedetection of whether the process described above has been used in themanufacture of the compound of formula (1), said method comprisingobtaining a sample from a medicament primarily containing the compoundof formula (1) as active ingredient, and applying a suitable analyticalmethod in order to detect whether said sample contains the compound offormula (B), wherein the presence of any amount of the compound offormula (B) indicates that said process has been used.

The compound of formula (1) shows potential as an active pharmaceuticalingredient, as inter alia described in WO 2007002433 and WO 2007002325.Consequently, in a further embodiment of the present invention, there isprovided a pharmaceutical preparation comprising the compound of formula(1) together with detectable amounts of at least compound of formula(B). More particularly there is provided a composition comprising thecompound of formula (1) in an amount greater than 99% by weight and thecompound of formula (B) in amounts from about 0.01% to about 0.15% byweight. Said composition may be further processed with pharmaceuticallyacceptable adjuvants to give any kind of pharmaceutical preparations asinter alia described in WO 2007002433 and WO 2007002325.

The starting materials, solvents, catalysts and auxiliary reagents usedin the method according to the present invention (see i.e. scheme 1) arecommercially available. However, when produced on a large industrialscale, there remains a need to also obtain large amounts of startingmaterials in good quality and high yields.

Consequently, according to the present invention, there are alsoprovided improved methods of making azaindole derivatives which arehalogenated at their 5-position, in particular 5-bromo-7-azaindole ((3),CAS 183208-35-7) and 5-chloro-7-azaindole (CAS 866546-07-8).5-Bromo-7-azaindole is a useful starting material in the above-mentionedprocess according to scheme 1.

Consequently, in a further embodiment according to the present inventionthere is provided a process for the manufacture of compound (I),

comprising the steps of:aa) reacting the compound of formula (II),

with the compound of formula (III),

in the presence of a catalyst, copper(I)iodide and a base, to producethe compound of formula (IV),

bb) reacting said compound of formula (IV) in the presence of aqueousalkali metal hydroxide at 50-90° C. and under reduced pressure toproduce the compound of formula (V)

andcc) reacting said compound of formula (V) in the presence of aqueousalkali metal hydroxide or a strong base to produce the compound offormula (1);whereinR¹ and R² are each independently selected from a C1-C4 alkyl, and

X is —Br or —Cl.

In one particularly preferred embodiment according to the presentinvention, the above process aa) to cc) is carried out with X being —Br.

In another particularly preferred embodiment according to the presentinvention, the above process aa) to cc) is carried out with X being —Cl.

In still another preferred embodiment according to the present inventionR₁ and R₂ are both methyl.

The synthesis of compounds of formula (1) as described above is asequential process. After each reaction described in steps aa) to cc),aqueous work-up procedures are applied and the formed intermediateproduct is optionally being isolated. In an alternative setup it is alsopossible to carry out the reaction steps bb) and cc) almostsimultaneously. This means the conversion of compound (V) into compound(I) starts as soon as compound (V) is formed, and before the reaction toobtain compound (V) (step bb)) is terminated. Therefore, the tworeaction steps bb) and cc) may run under the same reaction conditions.Consequently, no work-up of compound (V) prior to its further reactionto compound (I) is required according to this alternative method.

Therefore, in yet another embodiment there is provided a method toobtain the compound of formula (1) directly from formula (IV) withoutthe need to apply an aqueous work-up on the stage of the compound offormula (V). This can be achieved by adding to the compound of formula(IV), dissolved in an approximately 1:1 (w/w) mixture of water andN-methylpyrrolidone (NMP), 5 to 10 equivalents of aqueous sodiumhydroxide at about 75 to about 85° C. while applying a pressure of about350 mbar, followed by stirring at about 75 to about 85° C. and underreduced pressure (<400 mbar) for 15 to 20 hours. During the entirereaction time distilled acetone/water is continuously replaced by water.The termination of the reaction can be monitored by taking a sample outof the reaction mixture after 15 to 20 hours and analyzing said samplewith HPLC. A specific procedure for this reaction is disclosed inExample 7b.

The term “C1-C4 alkyl” as used herein means a linear or branchedsaturated hydrocarbon, such as for example methyl, ethyl, propyl,i-propyl, n-butyl, 2-butyl, tert-butyl, with methyl being especiallypreferred.

The term “alkali metal hydroxide” as used herein means sodium-, lithium-or potassium hydroxide, with lithium- and sodium hydroxide beingespecially preferred.

The term “reduced pressure” as used herein means <500 mbar, preferably<400 mbar.

The term “catalyst” as used herein in step aa) means any Pd(II)- orPd(0)-catalyst usually used in this type of Sonogashira reaction.Examples of such catalysts are Pd(PPh₃)₄, PdCl₂(PPh₃)₂, Pd(OAc)₂,Pd₂(dba)₃ with bis-(triphenylphosphine)-palladium(II)-dichloride(PdCl₂(PPh₃)₂) being especially preferred.

The term “base” as used herein in step aa) means weak bases as forexample N-methylmorpholine or trialkyl-amines, with triethylamine beingespecially preferred.

The term “strong base” as used herein in step cc) means alkali metalalcoholates, preferably potassium tert.-butylate.

In an embodiment of the invention, step bb) is carried out under reducedpressure below 100 mbar.

In an embodiment, the catalyst in step aa) is PdCl₂(PPh₃)₂ and thealkali metal hydroxide in step bb) is lithium- or sodium hydroxide.

In an embodiment, the compound of formula (IV) is dissolved in a mixtureof water and N-methylpyrrolidone, and is reacted in the presence ofaqueous sodium hydroxide at about 75 to about 85° C. and under reducedpressure for 15 to 20 hours to give directly the compound of formula (1)without the need to apply an aqueous work-up of the compound of formula(V).

In a particularly preferred embodiment according to the presentinvention, the above-mentioned reaction step aa) is carried out in thepresence of bis-(triphenylphosphine)-palladium(II)-dichloride,copper(I)iodide and triethylamine, the reaction step bb) is carried outwith aqueous lithium- or sodium hydroxide and the reaction step cc) iscarried out in the presence of potassium tert.-butylate or aqueoussodium hydroxide. The elimination of acetone (step bb) and subsequentring formation of step cc) are preferably carried out inN-methylpyrrolidone or in a mixture of N-methylpyrrolidone and water assolvent.

The process according to the reaction steps aa) to cc) is preferablycarried out according to the specific conditions and parameters given inExample 7a) or b). Consequently, the specific process according toExample 7a) or b) form each another preferred embodiment according tothe present invention.

The compounds of formula (II) can be obtained for example by iodinationof the corresponding 5-halogenated 2-amino-pyridines. Among the manyiodination conditions known to the skilled in the art a mixture ofiodine and periodic acid proved to be especially suitable for thementioned transformation.

The above described synthesis route via the compound of formula (IV) isa novel, alternative method for the production of the otherwise wellknown compounds of formula (1), in particular the 5-bromo-7-azaindole(3). A particular advantage of this process is the use of theintermediate compound of formula (IV) which can be easily purified andisolated from the reaction mixture. In addition, the use of compound(IV) avoids the release of environmentally hazardous Si by-products uponcyclization, which are formed if the correspondingtrimethylsilyl-ethynyl derivative is used, which is usually known forthis type of reaction (Sonogashira reaction) as inter alia described inWO 2009/016460 and US 2006/0183758.

The compounds of formula (IV) are thus valuable and novel intermediatesin the above-described synthesis to obtain 5-halogenated 7-azaindoles(I). Therefore, in yet another embodiment according to the presentinvention there is provided the compounds of formula (IV) as such.

The present invention is now illustrated by the following accompanyingworking examples. In some examples, the term “In-process control” isused. This term means that a sample is taken from the reaction mixturewhile the process is running, and said sample is being analyzed bystandard techniques known to the skilled person, preferably by HPLC, inorder to detect the degree of conversion of starting material intoproduct.

EXAMPLES Example 1 Step a Formation of Carboxylic Acid Chloride (Stepa) 1) According to Scheme 1)

-   55.8 g Sulfonamide Acid (2) was placed into a dried 1^(st) reaction    vessel kept under nitrogen atmosphere, to which-   280 mL methylenchloride were added. Then-   619 μL DMF were added to the obtained suspension and the resulting    mixture was kept at a temperature between 18-22° C. Then,-   25.4 g oxalylchloride were dissolved in-   66 mL methylenchloride, and this solution was slowly added over    approximately 30 minutes to the above-mentioned suspension whereby    the temperature of said suspension was kept between 18-22° C. The    formation of CO₂ and CO could be observed during said addition. The    reaction mixture was then further stirred for about 4 to 6 hours and    further kept at a temperature between 18-22° C. until the suspension    almost entirely turned into a solution and no gas formation could be    observed any more.

Friedel-Crafts-Acylation

-   -   In parallel to the above described formation of the        acid-chloride, a 2^(nd) reaction vessel was prepared, wherein

-   106.7 g aluminiumtrichloride were mixed together with

-   266 mL methylenchloride to produce a suspension which was then    cooled down to about −12 to 2° C. In parallel, a suspension of

-   39.4 g 5-bromo-7-azaindole in

-   66 mL methylenchloride was prepared in a 3^(rd) dried reaction    vessel under nitrogen atmosphere. Said bromoazaindole suspension was    added to said aluminiumtrichloride suspension over approximately 30    minutes and at a temperature between −12 to 2° C.    -   The obtained suspension was immediately further reacted by        addition of the acid-chloride solution as obtained according to        the procedure described above over approximately 30 minutes,        whereby the reaction mixture was allowed to warm up to about        20-25° C. using the spontaneous heat release observed upon        addition of the said acid chloride solution. After addition of        the acid-chloride solution, the reaction mixture was further        stirred over approximately 8 to 10 hours; whereby the mixture        was kept at a temperature between 20-25° C. During this time a        separation into 2 phases was observed.    -   Meanwhile, a 4^(th) reaction vessel was prepared, containing

-   400 ml water which was cooled to a temperature between 0-5° C. The    two phase reaction mixture as obtained according to the preceding    steps was added slowly, over approximately 30 minutes, to said    cooled water into said 4^(th) reaction vessel whereby the resulting    mixture was kept at a temperature between 0-20° C. This resulted in    an exothermic reaction and precipitation of the compound of    formula (4) from the resulting biphasic reaction mixture.    -   Methylene chloride was widely removed by distillation under        reduced pressure from the heterogeneous mixture. Then the        aqueous suspension of the compound of formula (4) was diluted        with methylene chloride and THF. A clear biphasic mixture was        obtained by heating the reaction mixture to about 50° C. After        phase separation the organic phase was washed twice with 400 ml        semi-saturated brine at about 50° C. The organic phase was        concentrated under reduced pressure at about 50° C. to a volume        of about 400 ml whereby crystallization of the compound of        formula (4) started.

-   600 ml Heptane was added within about 30 min at about 50° C. The    resulting suspension was cooled in about 3-5 h to ca. 0° C. After    stirring for at least one additional hour at ca. 0° C. to complete    the crystallization, the suspension was filtered and the wet    precipitate was washed two times with

-   120 mL n-heptane. The wet product was dried in vacuum and at a    temperature between 50-60° C.

Yield: 85 g (=90%) light beige colored, crystalline azaindole (4).

Example 2 Step b Formation of Compound (5)

45.8 g of the compound (4) as obtained according to Example 1 weresuspended in

600 ml toluene. Water as contained in the suspension was removed at atemperature between 60-80° C. and under reduced pressure of 450-400mbar. Subsequently,

200 ml toluene were newly added and the suspension was cooled to 20-25°C. Then, a solution of

1.22 g dimethylaminopyridine in

20 ml toluene was added, prior to the addition of

15.8 g n-tripropylamine. Subsequently,

22.0 g 2,6-dichlorobenzoylchloride were slowly added via a droppingfunnel over approximately 15 minutes while the mixture was kept between20 and 25° C.

The reaction mixture was stirred for about 1-2 hours at a temperaturebetween 20-25° C., whereby the color of the mixture turned into brown.

The brownish reaction mixture as obtained by the last step above, wasdiluted with

275 ml water and subsequently with

29.6 g hydrochloric acid (37%). The resulting two phase mixture washeated to 65-70° C. The two phases were allowed to separate after about10 minutes. The toluene phase was washed at a temperature between 65 and70° C., first with

300 ml of an aqueous solution containing 10% sodium hydrogencarbonate,and then with

300 ml water. The organic (toluene) phase was concentrated byevaporation at temperatures between 55 and 60° C. and at reducedpressure (200-80 mbar) to a volume of about 200 ml. During thisprocedure the crude product (5) precipitated due to crystallization. Theresulting suspension was then slowly cooled down (within about 5 h) to−5 to 0° C. and further stirred at that temperature for 1 h. The crudeproduct was separated by filtration, washed twice with

30 ml toluene (0° C.), and was subsequently dried at 50-55° C. and 26-13mbar.

Yield: 57 g (90%) of compound of formula (5).

Example 3 Step c Formation of Compound (6), Suzuki-Coupling

-   23.16 g 4-Chlorphenylboronic acid (5a) were mixed with-   85.00 g of compound (5) as obtained according to Example 2 in a    dried 1^(st) reaction vessel under nitrogen atmosphere. To the    resulting suspension were further added-   395 ml anisole.    -   The suspension was kept at room temperature (20-25° C.) and        mixed with a solution of-   57.08 g sodium carbonate in-   337 ml water. The reaction mixture was then heated to a temperature    of 70+/−2° C. At this temperature,-   0.236 g bis-(triphenylphosphin)-palladium(II)-dichloride together    with-   110 ml anisole were added to the reaction mixture, which was    subsequently slowly (within about 60 minutes) heated up to a    temperature between 80-88° C. (Heating Temperature outside did not    exceed 110° C.) and stirred for about 2 h. Towards the end of the    reaction the formation of a clear two phase reaction mixture with a    dark red upper (organic) phase was obtained.    -   After completion of the reaction, the reaction mixture was        cooled down to 60-80° C. and transferred via a filter into a 2nd        reaction vessel. The 1st reaction vessel and the filter were        washed with-   110 ml warm anisole which was added to the 2^(nd) reaction vessel.    The obtained two phases were separated and the organic phase was    washed at 60-80° C., first with-   375 ml 0.1 N sulfuric acid containing 10% (w/w) sodium sulfate, and    subsequently with-   375 ml water. During the last extraction, reversal of the two phases    was observed. The organic phase was now the lower phase. In order to    obtain complete phase separation, the last extraction was carried    out at a temperature of at least 70° C. The obtained orange-yellow    solution was concentrated at reduced pressure to about 225 mL    (+/−10%), while the temperature of the solution was kept between    60-80° C. Subsequently, the resulting suspension was cooled to about    60° C. Then, over a period of about 30 minutes,-   628 ml methanol were continuously added. Subsequently, the    suspension was slowly (within about 4 hours) cooled to 0° C. (+/−2°    C.), and stirred for another 3 hours at that temperature until    complete crystallization of the product of formula (6) occurred. The    suspension was separated by filtration, and the wet solid residue    was washed two times with-   112 ml cold methanol.    -   The wet chlorophenylbenzamide (6) was dried in a rotary        evaporator under reduced pressure and at a water bath        temperature between 70-80° C.

Yield: 74-76 g (82-85%) almost colorless, crystallineChlorophenylbenzamide (6). The product can be optionally re-crystallizedfrom toluene for further purification.

¹H-NMR (400 MHz, CDCl3): δ ppm 1.09 (t, J=7.5 Hz, 3H), 1.86-1.99 (m,2H), 3.10-3.19 (m, 2H), 6.53 (s, 1H), 7.11 (dt, J=8.6, 1.5 Hz, 1H),7.39-7.49 (m, 5H), 7.50-7.59 (m, 2H), 7.79 (td, J=9.0, 5.6 Hz, 1H), 8.32(br. s, 1H), 8.43 (br. s, 1H), 8.84 (d, J=2.3 Hz, 1H).

Example 4 Step d Formation of Compound (1)

-   70.0 g Chlorphenylbenzamide (6),-   175 ml DMA and-   88 ml methanol were placed into a dried reaction vessel under    nitrogen atmosphere.    -   The resulting suspension was kept at 20-25° C., and mixed with-   48.0 g of a solution of ammonia in methanol (15%). The autoclave was    then closed and the reaction mixture heated to 50-55° C., which    resulted in the formation of a clear solution. The temperature was    maintained while stirring the reaction mixture for about 10-20    hours. Subsequently, the clear solution was transferred into a    double jacket reaction vessel, and further diluted with-   254 ml methanol. The reaction mixture was then concentrated to its    original volume under reduced pressure and (600-500 mbar) at a    jacket-temperature of maximum 60° C. Subsequently,-   508 ml methanol were newly added slowly over a period of about 20-30    minutes, whereby the temperature of the reaction mixture was kept    between 45-55° C. The resulting suspension was slowly cooled down    (within about 2 hours) to 20° C. (±3° C.) and subsequently was    further stirred for at least 1 hour prior to separation of the solid    reaction product (1) by filtration. The filter cake was washed two    times with-   120 mL methanol. The wet product was dried in rotary evaporator    under reduced pressure and while applying a water bath temperature    of 50 to 60° C.

Yield: 49 g (95%) of the white, crystalline compound formula (1).

¹H-NMR (600 MHz, CDCl3): δ ppm 1.07 (t, J=7.5 Hz, 3H), 1.84-1.98 (m,2H), 3.07-3.17 (m, 2H), 6.41 (s, 1H), 7.06 (dt, J=8.6 Hz, 1.5 Hz, 1H),7.46-7.51 (m, 2H), 7.60-7.64 (m, 2H), 7.70 (td, J=9.0, 5.5 Hz, 1H), 7.73(d, J=2.7 Hz, 1H), 8.65 (d, J=2.2 Hz, 1H), 8.88 (d, J=1.9 Hz, 1H), 9.55(br. s, 1H).

Purity: ≧99% (m/m, HPLC); Palladium content ≦5 ppm; compound (B): about0.1%

Example 5 Preparation of 2-amino-5-bromo-3-iodopyridine (IIa)

-   -   In a 1000 mL double-jacket reactor (under a nitrogen atmosphere)

-   38.28 g iodine is suspended in

-   21 g acetic acid and

-   62 g acetonitrile. To the brown mixture is added at 20 to 40° C.

-   14.6 g sulfuric acid 96%. The addition is strongly exothermic. The    dropping funnel is rinsed with

-   20 g water. The resulting mixture is heated with a jacket    temperature of 90° C. When the temperature of the mixture is 70° C.,    the mixture is treated within 3 to 6 minutes with

-   45.20 g periodic acid (50% in water). The addition is endothermic.    The funnel is rinsed with

-   10 g water. The solution is then treated at 65 to 75° C. within 5 to    10 minutes with a previously prepared solution of

-   58.00 g 2-amino-5-bromopyridine in

-   67 g acetonitrile and

-   31.5 g acetic acid. The dropping funnel is rinsed with

-   15 g acetonitrile. The resulting solution is heated to 77 to 82° C.    and stirred under slightly reflux conditions for 3 to 4 hours    (approx. 90° C. jacket temperature). In-process control (proposed    target value: <2.0% starting material). Upon complete conversion the    mixture is immediately cooled down and treated at 60 to 70° C. drop    wise with

-   66 g sodium hydrogen sulfite (38-40% in water). Immediately after    the addition, the mixture is diluted at 60 to 70° C. within 30 to 60    minutes with

-   360 g water. The mixture is then treated at 60 to 70° C. within 50    to 90 minutes with approximately

-   ˜202 g sodium hydroxide 28% to adjust the pH to 7.3 to 7.6. When the    desired pH is reached the suspension is stirred at 60 to 70° C. for    30 to 60 minutes. The suspension is cooled to 20 to 25° C. within 2    to 5 hours and then stirred at this temperature for 2 to 5 hours.    The crystals are filtered off and washed in two portions with a    mixture of

-   270 g water and

-   23 g acetonitrile. The wet crystals (approx. 120 g) are dried at 40    to 50° C./<30 mbar until constant weight.

Yield: 90.5 g of slightly brownish crystals with an assay of 95.0%(m/m). This corresponds to a corrected yield of 86%.

Example 6 a) Preparation of4-(2-Amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol

A suspension of 2-amino-5-bromo-3-iodopyridine (10.0 g, 33.5 mmol),bis-(triphenylphosphine)-palladium(II)-dichloride (117 mg, 0.17 mmol),copper(I)iodide (79 mg, 0.41 mmol) and triethylamine (6.1 mL, 43.5 mmol)in dichloromethane (40 mL) was treated at 23 to 30° C. within 1 to 2hours with a solution of 1,1-dimethyl-2-propyn-1-ol (3.70 g, 44 mmol) indichloromethane (10 mL) and the resulting mixture was stirred at 25° C.for 3 hours. The mixture was diluted with dichloromethane (20 mL) andwashed with water (2×50 mL). The organic phase was then treated with 1 MHCl (80 mL). The layers were separated and the organic layer wasextracted with 1 M HCl (20 mL). The combined product containing aqueouslayers were washed with dichloromethane (2×10 mL). The pH of the aqueouslayer was adjusted to pH 7-9 by the drop wise addition of sodiumhydroxide solution (28% in water, 18 g). The resulting suspension wasstirred at 20° C. for 2 hours and the crystals were then filtered offand washed with water (2×20 mL). The wet crystals were dried at 50°C./<30 mbar affording 6.99 g (82%) of4-(2-amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol as a melted masswith a purity of 99.5% (HPLC, area %). ¹H NMR (400 MHz, CDCl₃): δ ppm1.63 (s, 6H); 4.0 (br., 3H); 7.59 (d, J=2.4, 1H); 8.03 (d, J=2.4, 1H).

b) Alternative Preparation of4-(2-Amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol

-   -   In a 1000 mL double-jacket reactor (under a nitrogen atmosphere)

-   84.0 g 2-amino-5-bromo-3-iodopyridine (96.4% (m/m)) is suspended in

-   900 g dichloromethane. The suspension is heated to reflux (45° C.    jacket temperature) and stirred at slightly reflux for 15 to 45    minutes. The diminished solution is cooled to 30 to 35° C. and then    polish-filtered (using a Zeta plus filter plate charged with    Decalite Speedex). The first reactor and the transfer pipe are    rinsed with

-   130 g dichloromethane (pre-heated to 30 to 35° C.). The clear    filtrate is concentrated to a residual volume of 260 to 300 mL. The    resulting suspension is treated at ca. 30° C. with

-   600 mg bis-(triphenylphosphine)-palladium(II)-dichloride,

-   400 mg copper(I)-iodide and

-   38.0 g triethylamine. The used receivers are rinsed with

-   10 g dichloromethane. The brown suspension is treated at 30 to    34° C. within 1 to 2 hours with a solution of

-   32.0 g 2-methyl-3-butin-2-ol in

-   120 g dichloromethane. The dropping funnel is rinsed with

-   15 g dichloromethane. The mixture is stirred for 10 hours at 30 to    34° C. In-process control. Upon complete conversion the mixture is    diluted at 30 to 34° C. with

-   240 g dichloromethane and

-   200 g water and treated at 28 to 34° C. within 10 to 20 minutes with

-   100 g ammonium hydroxide solution (25% in water). The biphasic    solution (ca. 950 mL) is stirred for 15 to 30 minutes at 28 to    34° C. and the layers are then allowed to separate for 15 to 30    minutes. The organic layer is separated and the aqueous layer is    extracted at 28 to 34° C. with

-   80 g dichloromethane. The combined organic layers are diluted at 30    to 34° C. with

-   100 g water and then treated at 28 to 34° C. within 10 to 20 minutes    with

-   50 g ammonium hydroxide solution (25% in water). The biphasic    solution is stirred for 15 to 30 minutes at 28 to 34° C. and the    layers are then allowed to separate for 15 to 30 minutes. The    organic layer is separated and then washed at 28 to 34° C. with

-   100 g water. The organic layer is concentrated under reduced    pressure and at a maximum temperature of 34° C. to a volume of 550    to 600 mL. The organic layer is diluted at 25 to 32° C. with

-   400 g water and treated at 25 to 32° C. within 15 to 30 minutes with

-   45 g hydrochloric acid (37% in water). The biphasic solution (980    mL) is stirred for 15 to 30 minutes at 25 to 32° C. and the layers    are then allowed to separate for 30 to 60 minutes. The layers are    separated and the organic layer is diluted with

-   225 g water and then treated at 25 to 32° C. within 15 to 30 minutes    with

-   25 g hydrochloric acid (37% in water). The combined product    containing aqueous layers are washed at 25 to 32° C. with

-   100 g dichloromethane. From the aqueous layer dichloromethane is    then azeotropically removed with water under reduced pressure and at    a maximum internal temperature of 32° C. At the end of the    distillation a volume of 550 to 600 mL is adjusted. The resulting    aqueous solution is polish-filtered (using a Zeta plus filter    plate). The first reactor and the transfer pipes are rinsed with

-   40 g water. The clear solution is then treated at 22 to 30° C.    within 60 to 120 minutes with approximately

-   54 g sodium hydroxide (28% in water) until the pH is adjusted to pH    7.5 to 9.5. This forces the product to precipitate. After the dosing    the resulting suspension is stirred at 20 to 25° C. for 4 to 16    hours. The crystals are filtered off and washed in two portions with

-   300 g water. The wet crystals (ca. 73 g) are dried at 40 to 50° C.    and <30 mbar until constant weight.

Yield: 65.04 g (93%) of yellow crystals with a content of 98.6% (m/m).This intermediate can optionally be re-crystallized fromisopropanol/water for further purification.

¹H NMR (400 MHz, CDCl₃): δ ppm 1.61 (s, 6H); 2.3 (br., 1H); 4.9 (br.,2H); 7.57 (d, J=2.4, 1H); 8.01 (d, J=2.4, 1H).

Example 7 a) Preparation of 5-bromo-7-azaindole (3 or Ia) from isolated2-amino-5-bromo-3-iodopyridine

A suspension of 2-amino-5-bromo-3-iodopyridine (5.0 g, 16.7 mmol),bis-(triphenylphosphine)-palladium(II)-dichloride (43 mg, 0.061 mmol),copper(I)iodide (29.4 mg, 0.15 mmol) and triethylamine (2.21 g, 21.8mmol) in dichloromethane (20 mL) was treated at 23 to 30° C. within 1 to2 hours with a solution of 1,1-dimethyl-2-propyn-1-ol (1.85 g, 21.7mmol) in dichloromethane (10 mL) and the resulting mixture was stirredat 25° C. for 4 hours. The mixture was diluted with dichloromethane (10mL) and washed with water (2×25 mL). The organic phase was then treatedwith 1 M HCl (40 mL). The layers were separated and the organic layerwas extracted with 1 M HCl (15 mL). The combined product containingaqueous layers were washed with dichloromethane (2×8 mL). The pH of theaqueous layer was adjusted to pH 7-9 by the drop wise addition of sodiumhydroxide solution (28% in water). The resulting suspension was stirredat 20° C. over night and the crystals were then filtered off and washedwith water (2×5 mL). The wet crystals were dissolved inN-methylpyrrolidone (50 mL) and treated within 2 hours at 60° C. and50-100 mbar with an aqueous solution of lithium hydroxide (2.4 M, 32mL). The resulting mixture was heated to 75° C. and stirred at thistemperature and under reduced pressure (50-100 mbar) for 15-20 hours.Toluene (20 mL) and water (20 mL) were then added and the layers wereseparated. The aqueous layer was extracted with toluene (3×25 mL). Thecombined organic layers were washed with water (3×10 mL) and thenconcentrated to dryness. The residue was dissolved inN-methylpyrrolidone (50 mL) and treated at 60° C. with potassiumtert.-butylate (3.52 g, 30.7 mmol). After stirring for 3 hours at 60°C., the mixture was cooled to ambient temperature and diluted withtoluene (40 mL) and water (40 mL). The aqueous layer was separated andback extracted with toluene (3×50 mL). The combined toluene layers werewashed with water (3×10 mL) and then concentrated to dryness. Theresidue was dissolved in a hot mixture of toluene and n-heptane (20 mL).The clear solution was cooled to −5° C. within 4 to 6 hours whereuponcrystals precipitated. The suspension was stirred at −5° C. for 2-4hours. The crystals were filtered off, washed with heptane and dried at45° C./<30 mbars over night to afford 5-bromo-7-azaindole (2.05 g, 62%yield) as slightly yellow crystals with a purity of 99.6% (HPLC, area%).

b) Preparation of 5-bromo-7-azaindole from isolated4-(2-Amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol

-   -   A 1000 mL double-jacket reactor (under a nitrogen atmosphere) is        charged with

-   80.0 g 4-(2-amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol,

-   320 mL N-methylpyrrolidone and

-   330 mL water. The mixture is heated to 75 to 80° C. and a vacuum of    ca 350 mbar is applied. The solution is then treated at 75 to 80° C.    within 30 to 45 minutes with

-   181 mL sodium hydroxide (28% in water). The dropping funnel is    rinsed with

-   5 mL water and the mixture stirred at 78 to 81° C. for 15 to 20    hours. During stirring the jacket temperature and the vacuum have to    be adjusted such that the internal temperature is 78 to 81° C. and a    slight steadily distillate flow is guaranteed. When the volume in    the reactor has reached approx. 800 mL water is continuously added    to keep the volume constant for the rest of the reaction time.    In-process control. Upon complete conversion, the reaction mixture    is concentrated to a volume of approx. 700 mL and then cooled to 50    to 55° C. The mixture is treated at this temperature with

-   200 mL toluene. The biphasic mixture (ca. 900 mL) is stirred at 50    to 55° C. for 15 to 30 minutes and the layers are then allowed to    separate for 15 to 30 minutes. The aqueous layer is separated and    then extracted at 50 to 55° C. with 3×140 mL, totally with

-   420 mL toluene. The combined toluene layers are washed at 50 to    55° C. with 2×100 mL, totally with

-   200 mL water. The toluene layer is concentrated under reduced    pressure at 45 to 55° C. until a residual volume of 450 to 500 mL is    obtained. The residue is treated at 50 to 55° C. with

-   225 g ethyl acetate and the resulting solution is washed at 50 to    55° C. with 3×150 mL, totally with

-   450 mL water. From the organic layer, water and ethyl acetate are    azeotropically distilled off with toluene under reduced pressure at    45 to 55° C. At the end of the distillation a volume of 600 to 700    mL is adjusted. The mixture is heated to 90 to 95° C. and stirred    until a clear solution is obtained. The solution is treated with

-   2.0 g activated charcoal (Norit SX) and the resulting mixture    stirred for 15 to 30 minutes at 90 to 95° C. The charcoal is removed    by a hot filtration at 90 to 95° C. The first reactor, the filter    and the transfer pipes are washed with 3×100 mL, totally with

-   300 mL toluene. The filtrate is concentrated under reduced pressure    to a volume of approx. 400 mL. The resulting suspension is heated to    90 to 100° C. to obtain a clear solution. The solution is cooled to    −5 to −10° C. within 7 to 10 hours and the resulting suspension    stirred at this temperature for additional 3 to 5 hours. The    crystals are filtered off and washed in two portions with

-   120 mL toluene (pre-cooled to <0° C.). The wet crystals are dried at    55 to 65° C./<30 mbar until constant weight.

Yield: 46.5 g (75%) of slightly yellow crystals with an assay of 100.1%(m/m).

Example 8 Preparation of 5-chloro-7-azaindol (Ib) Step 1: Synthesis of2-Amino-5-chloro-3-iodopyridine (IIb)

-   -   In a 1000 mL double-jacket reactor under a nitrogen atmosphere

-   38.28 g iodine is suspended in

-   21 g acetic acid and

-   62 g acetonitrile. To the brown mixture is added at 20 to 40° C.

-   14.6 g sulfuric acid 96%. The addition is strongly exothermic. The    dropping funnel is rinsed with

-   20 g water. The resulting mixture is heated with a jacket    temperature of 90° C. When the temperature of the mixture is 70° C.,    the mixture is treated within 3 to 6 minutes with

-   45.20 g periodic acid (50% in water). The addition is endothermic.    The funnel is rinsed with

-   10 g water. The solution is then treated at 65 to 75° C. within 5 to    10 minutes with a previously prepared solution of

-   43.1 g 2-amino-5-chloropyridine in

-   67 g acetonitrile and

-   31.5 g acetic acid. The dropping funnel is rinsed with

-   15 g acetonitrile. The resulting solution is heated to 77 to 82° C.    and stirred under slightly reflux conditions for 4 hours (approx.    90° C. jacket temperature). The mixture is then cooled 60-65° C. and    treated with

-   66 g sodium hydrogen sulfite (39% in water). After the addition, the    mixture is diluted at 60 to 70° C. within 10 to 20 minutes with

-   360 g water. The mixture is then treated with

-   162 mL sodium hydroxide 28% to adjust the pH to pH 7.4 and the    resulting suspension is stirred at 50° C. for 30 to 60 minutes. The    suspension is cooled to 20 to 25° C. within 2 hours and then stirred    at this temperature over night. The crystals are filtered off and    washed in two portions with a mixture of

-   270 g water and

-   23 g acetonitrile. The wet crystals (approx. 110 g) are dried at    40-50° C./<30 mbar to afford 72.5 g (85%) of slightly brownish    crystals with a purity of 94.8% (area).

Step 2: Synthesis of4-(2-Amino-5-chloro-pyridin-3-yl)-2-methyl-but-3-yn-2-ol

-   -   In a 1000 mL double-jacket reactor

-   38.0 g 2-amino-5-chloro-3-iodopyridine is suspended in

-   120 mL dichloromethane. The suspension is treated at ca 30° C. with

-   0.60 g bis-(triphenylphosphine)-palladium(II)-dichloride,

-   0.41 g copper(I)-iodide and

-   27.5 mL triethylamine. The used receivers are rinsed with

-   10 g dichloromethane. The brown suspension is treated at 30 to    34° C. within 1 to 2 hours with a solution of

-   16.8 g 2-methyl-3-butin-2-ol in

-   60 mL dichloromethane. The dropping funnel is rinsed with

-   5 mL dichloromethane. The mixture is stirred for 3 hours at 30 to    34° C. and then treated at 30 to 34° C. with

-   100 mL dichloromethane and

-   150 mL ammonium hydroxide solution (10% in water). The biphasic    solution is stirred for 10 to 20 minutes at 30 to 34° C. and the    layers are then allowed to separate for 15 to 45 minutes. The    organic layer is separated and the aqueous layer is extracted at 30    to 34° C. with

-   40 mL dichloromethane. The combined organic layers are washed at 28    to 34° C. with

-   150 mL ammonium hydroxide solution (10% in water) and then with

-   150 mL water. The organic layer is then treated at 25 to 32° C. with

-   300 mL hydrochloric acid (1.0 M in water). The biphasic solution is    stirred for 20 to 30 minutes at 25 to 32° C. and the layers are then    allowed to separate for 30 to 60 minutes. The organic layer is    separated and extracted at 25 to 32° C. with

-   100 mL hydrochloric acid (1.0 M in water). The combined product    containing aqueous layers are washed at 25 to 32° C. with

-   100 mL dichloromethane. From the aqueous layer dichloromethane is    then azeotropically removed with water under reduced pressure and at    a maximum internal temperature of 30° C. The aqueous solution is    then treated at 22 to 30° C. within 60 to 120 minutes with    approximately

-   32 mL sodium hydroxide (28% in water) until the pH is adjusted to    pH 9. This forces the product to precipitate. After the dosing the    resulting suspension is stirred at 20 to 25° C. over night. The    crystals are filtered off and washed in two portions with

-   150 g water. The wet crystals (40.2 g) are dried at 40 to 50° C. and    <30 mbar until constant weight to afford 29.2 g (92%) of slightly    brownish crystals with a purity of 98.7% (area).

Step 3: Synthesis of 5-chloro-7-azaindol (Ib)

-   -   A 500 mL double-jacket reactor (under a nitrogen atmosphere) is        charged with

-   25.0 g 4-(2-amino-5-chloro-pyridin-3-yl)-2-methyl-but-3-yn-2-ol,

-   120 mL N-methylpyrrolidone and

-   130 mL water. The mixture is heated to 75 to 80° C. (ca. 95° C.    jacket temperature) and a vacuum of ca. 350 mbar is applied. The    solution is then treated at 75 to 80° C. within 30 to 45 minutes    with

-   85 mL sodium hydroxide (28% in water). The dropping funnel is rinsed    with

-   5 mL water and the mixture stirred at 78 to 81° C. over night.    During stirring the jacket temperature and the vacuum have to be    adjusted such that a slight steadily distillate flow is guaranteed.    In a typical lab experiment approx. 50 mL of water/acetone are    distilled off in 2 hours. During the reaction, water is continuously    added to keep the volume constant at approx. 270 mL. Upon complete    conversion, the reaction mixture is cooled to 50 to 55° C. The    mixture is treated at this temperature with

-   60 mL toluene. The biphasic mixture is stirred at 50 to 55° C. for    15 to 30 minutes and the layers are then allowed to separate for 15    to 30 minutes. The aqueous layer is separated and then extracted at    50 to 55° C. with 3×50 mL with    -   toluene. The combined toluene layers are washed at 50 to 55° C.        with 5×40 mL with    -   water. The toluene layer is concentrated to dryness. The residue        (17.3 g) is crystallized from

-   90 mL toluene to afford 13.0 g (71%) of 5 chloro-7-azaindol (Ib) as    slightly yellow crystals with a purity of 96.7% (area).

1. A process for the manufacture of the compound of formula (1),

comprising the steps of reacting the compound of formula (5),

with 4-chlorophenylboronic acid in the presence of a palladium Catalystto produce the compound of formula (6),

and cleaving the 2,6-dichlorobenzamide group in said compound of formula(6) to produce the compound of formula (1).
 2. The process according toclaim 1, wherein the compound of formula (5) is obtained by: reactingthe compound of formula (2),

with oxalylchloride to produce the corresponding acid chloride; reactingsaid acid chloride with 5-bromo-7-azaindole in the presence of aluminiumtrichloride to produce the compound of formula (4),

and reacting said compound of formula (4) with2,6-dichlorobenzoylchloride to produce the compound of formula (5). 3.The process according to claim 1, wherein: (A) said compound of formula(5) is obtained by: reacting the compound of formula (2)

with oxalylchloride in the presence of methylenechloride andN,N-Dimethylformamide to produce the corresponding acid chloride;reacting said acid chloride with 5-bromo-7-azaindole in the presence ofaluminium trichloride to produce the compound of formula (4)

and reacting said compound of formula (4) with dichlorobenzoylchloridein the presence of dimethylaminopyridine and n-tripropylamine to producethe compound of formula (5)

and (B) said cleavage of the 2,6-dichlorobenzamide group in saidcompound of formula (6) is accomplished by reacting said compound withammonia in methanol or ethanol solution diluted with a polar aproticsolvent.
 4. The compound of formula (A)


5. The compound of formula (B)


6. A composition comprising the compound of formula (1),

and the compound of formula (B),


7. A composition according to claim 6, wherein said compound of formula(B) is present in an amount of from about 0.02% to about 0.15% byweight.
 8. An analytical method for the detection of whether the processaccording to claim 1 has been used in the manufacture of the compound offormula (1), said method comprising obtaining a sample from a medicamentprimarily containing the compound of formula (1) as active ingredient,and applying a suitable analytical method in order to detect whethersaid sample contains the compound of formula (B), wherein the presenceof any amount of the compound of formula (B) indicates that the processaccording to claim 1 has been used.
 9. A process for the manufacture ofcompound (I),

comprising the steps of: aa) reacting the compound of formula (II),

with the compound of formula (III),

in the presence of a catalyst, copper(I)iodide and a base, to producethe compound of formula (IV),

bb) reacting said compound of formula (IV) in the presence of aqueousalkali metal hydroxide at 50-90° C. and under reduced pressure toproduce the compound of formula (V),

and cc) reacting said compound of formula (V) in the presence of aqueousalkali metal hydroxide or a strong base to produce the compound offormula (I); wherein R¹ and R² are each independently a C1-C4 alkyl, andX is —Br or —Cl.
 10. The process according to claim 9, wherein X is —Br.11. The process according to claim 9, wherein R¹ and R² are both methyl.12. The process according to claim 10, wherein reaction step bb) iscarried out under reduced pressure below 100 mbar.
 13. The processaccording to claim 9, wherein the catalyst in step aa) is PdCl₂(PPh₃)₂and the alkali metal hydroxide in step bb) is lithium- or sodiumhydroxide.
 14. The process according to claim 9, wherein the compound offormula (IV) is dissolved in a mixture of water and N-methylpyrrolidone,and is reacted in the presence of aqueous sodium hydroxide at about 75to about 85° C. and under reduced pressure for 15 to 20 hours to givedirectly the compound of formula (I) without the need to apply anaqueous work-up of the compound of formula (V).
 15. The compound offormula (IV),

wherein R¹ and R² are each independently a C1-C4 alkyl, and X is —Br or—Cl.